Life Extension with FGF21

[Gordo]

 

[Mike Lustgarten]

 

[Dean Pomerleau]

Thanks Gordo and Mike. Mike, you mention dietary interventions with the potential to increase levels of FGF-21, but you didn't mention cold exposure or the role of brown adipose tissue (BAT). I bet the follow-up video from Dr. Greger will have the same omission. But consider [1] (discussed here) which found that people exposed to just 12 hours of 66degF had a circulating FGF-21 level that was 37% higher than controls exposed to 75degF.

Increased thermogenesis is believed to be an (if not the) important mechanism by which FGF-21 improves metabolic health and by implication, longevity. This post and its embedded links discuss this relationship. In particular, there is a positive feedback loop (i.e. virtuous cycle) between FGF-21 and BAT induced by cold exposure (or exercise) - i.e. FGF-21 induces the browning of white adipose tissue and brown/beige adipose tissue in turn synthesizes and secretes FGF-21, at least when sufficient glucose/fat is available and ambient temperature is sufficiently low.

Here is a graphical summary of interplay between cold exposure, FGF-21, brown/beige adipose tissue, thermogenesis and improved metabolic health:

 

--Dean

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[2] J Clin Endocrinol Metab. 2013 Jan;98(1):E98-102. doi: 10.1210/jc.2012-3107. Epub 

2012 Nov 12.

 

Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm

in humans: relationship between FGF21 levels, lipolysis, and cold-induced

thermogenesis.

 

Lee P(1), Brychta RJ, Linderman J, Smith S, Chen KY, Celi FS.

 

Author information: 

(1)Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes

and Digestive and Kidney Diseases, National Institutes of Health, Building 10,

Clinical Research Center, 10 Center Drive, Bethesda, Maryland 20892, USA.

pcylee@gmail.com

 

CONTEXT: Cold exposure stimulates fibroblast growth factor 21 (FGF21) secretion

in animals, enhancing the cold-induced thermogenesis (CIT) response through

browning of white adipose tissue. In humans, the effects of cold exposure on

circulating FGF21 levels are unknown.

OBJECTIVE: Our objective was to evaluate the effects of mild cold exposure on

circulating FGF21 and its relationship with CIT and lipolysis in humans.

DESIGN AND SETTING: We conducted a randomized, single-blind, crossover

intervention study at the National Institutes of Health Clinical Center.

PARTICIPANTS: Participants were healthy adults.

INTERVENTION: Subjects were exposed to a 12-h exposure to 24 or 19 C in a

whole-room indirect calorimeter.

OUTCOME MEASURES: Energy expenditure, plasma FGF 21, nonesterified fatty acid,

and adipose tissue microdialysis glycerol concentrations were evaluated.

RESULTS: At 24 C, plasma FGF21 exhibited a diurnal rhythm, peaking at 0800 h [110

(59-178) pg/ml], and progressively dropped to a nadir at 1700 h [41 (21-71)

pg/ml, P < 0.0001] before rising at 1900 h [60 (11-81) pg/ml, P < 0.0001].

Exposure at 19 C lessened the diurnal reduction of FGF21 observed at 24 C from

0800-1700 h and augmented overall FGF21 levels by 37 ± 45% (P = 0.01). The change

in area under the curve plasma FGF21 between 19 and 24 C correlated positively

with the change in area under the curve adipose microdialysate glycerol (R(2) =

0.35, P = 0.04) but not with nonesterified fatty acid. Cold-induced increase in

FGF21 predicted greater rise in energy expenditure during cold exposure (β =

0.66, P = 0.027), independent of age, gender, fat mass, and lean mass.

CONCLUSIONS: Mild cold exposure increased circulating FGF21 levels, predicting

greater lipolysis and CIT. A small reduction in environmental temperature is

sufficient to modulate FGF21 diurnal rhythm in humans, which may mediate

cold-induced metabolic changes similar to those in animals.

 

PMCID: PMC3537100

PMID: 23150685

[Gordo]

Yes, BAT activation is key here.

[Mike Lustgarten]

Yes, good point about cold exposure, Dean! 

[Gordo]

 

[Ron Put]

I know that there are a few ardent proponents of cold exposure vests here, but I really have my doubts, based on what I read. Short-term cold exposure is certainly a stressor and this may be good or bad. Nicotine has somewhat similar effects, although contrary the cold exposure, in the short run it lowers stress and increases dopamine.

Heck, nicotine is great for brown fat too... 😄

The study cited above is short-term and I do not see how a conclusion about long-term overall benefit can be drawn from it. Plenty of population studies show increased adverse outcomes from extreme temperature exposure, but especially from cold. And even short-term exposure carries risks that are not worth it, IMO.

I'd argue that it's better to stick to a whole food plant-based diet and appropriate exercise.

[Gordo]

Ron, you are the only one talking about extreme cold. Also you brought up the same article before and we already discussed it. But you do have a point that we don't have any long term data on humans practicing cold exposure for longevity kind of like we don't have much data for humans practicing CR for longevity (or at least data that shows a significant positive result).   Also note that food can activate BAT and plays an important role in browning white fat, so its not just about cold, in fact I would argue that the combination of proper diet (BAT activating/browning foods) and mild cold are critically important to achieving optimal benefits:

https://www.sciencedaily.com/releases/2018/08/180829115544.htm

Exercise also plays a role, as well as eating just the right amount (not too little, not too much):

https://www.prevention.com/weight-loss/a20444117/how-to-increase-brown-fat/

I would suggest at a minimum, sit in a 63F (17C) room for two hours a day (a cold vest is a good alternative to wasting energy on air conditioning in warm climates, turning the thermostat down to 63 in winter works too). Most people will easily acclimate to these temperatures and feel good once they become cold adapted as described in the various published research.  Eating capsinoids may be an alternative to cold exposure that gets similar results.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726164/ (specifically mentions capsinoids and daily 2-hour cold exposure at 17°C)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477363/

https://www.jci.org/articles/view/68993

Edited March 25, 2022 by Gordo

[Ron Put]

21 hours ago, Gordo said:

I would suggest at a minimum, sit in a 63F (17C) room for two hours a day (a cold vest is a good alternative to wasting energy on air conditioning in warm climates, turning the thermostat down to 63 in winter works too). Most people will easily acclimate to these temperatures and feel good once they become cold adapted as described in the various published research.  Eating capsinoids may be an alternative to cold exposure that gets similar results.

I am merely pointing out that there is plenty of evidence to at least question the wisdom of the cold exposure claims made. As you note, there are other ways to activate BAT that do not constrict and stiffen one's blood vessels, from diet (including capsinoids) to exercise.

[Saul]

I'm inclined to agree with Ron.  I'm skeptical about CE.  (But I find it hard to sleep in a room with temperatures above 65 degrees F --  and my wife likes 71.  A problem.

  --  Saul

 

 

[Gordo]

 

[Saul]

Hi Gordo!

I take cold showers, right after working out, which I do almost daily.

IMO, CR, exercise and adequate sleep, is more important than CE (which isn't worthless).

  --- Saul

 

[Alex K Chen]

Does anyone want to take FGF21 plasmids? I have a friend who can admin them to you

[Gordo]

My layman's best guess is that vasoconstriction is only a problem for people with coronary artery disease (i.e. higher risk of a heart problem flaring up when they are under stress) but that is hardly the audience of this forum.  There is so much evidence of the benefits of cold exposure it seems extremely unlikely to be a net negative for one's health or longevity.